Research is continuing to develop an alpha-(N)-heterocyclic carboxaldehyde thiosemicarbazone with clinical potential. Emphasis is being placed on amino substituted derivatives which have the capacity to inhibit the enzyme ribonucleoside diphosphate reductase. Studies on the mechanism of inhibition of this enzyme system and of DNA synthesis in neoplastic cells are also being carried out. The mechanism of action of bioreductive alkylating agents in transplanted tumors is being studied; in particular, efforts are being concentrated on the effects of groups capable of altering the oxidation-reduction potentials of this class of agent to determine the capacities of these derivatives to inhibit the synthesis of the nucleic acids and to interfere with coenzyme Q requiring enzyme systems. Investigations are being conducted to ascertain the role of increased levels of alkaline phosphatase in the acquisition of resistance by neoplastic cells of animals and man to 6-thiopurines. Attempts are being made to develop an effective inhibitor of alkaline phosphatase to employ in combination with either 6-thioguanine or 6-mercaptopurine in an effort to overcome resistance to these agents.